This proposal will investigate the expression of the LIF gene in the human fetal pituitary., in adult pituitary and pituitary adenomas and in murine AtT-20 pituitary cells. Recently published data is presented demonstrating the expression of pituitary LIF mRNA and immuno-reactive protein. RNase protection assays, immunocytochemistry and double gold immunoelectronmicroscopy will be used to study the ontogeny of human fetal pituitary cell LIF distribution and its co-localization with pituitary trophic hormones. LIF expression in normal adult pituitary and pituitary adenomas will also be studied. LIF action on the pituitary will be tested by in vitro culture of human and murine pituitary cells and measuring pituitary hormone synthesis and secretion. Recently published data demonstrated marked induction of POMC mRNA and ACTH by LIF. Responses to LIF, and the related cytokine oncostatin M were tested with other inducers of ACTH, including CRH. The specificity of endogenous LIF paracrine action was tested by using antibodies to LIF and will be further tested by utilizing antibodies to LIF receptor and gp 130 (LIF signal transducer). LIF-induced phosphorylation of p91 (Stat-1), and its role in signaling the induction of POMC will be investigated. LIF may be an intrapituitary determinant of ACTH synthesis and secretion, playing a role in differentiation of the fetal pituitary. Mice expressing either a pituitary-directed LIF transgene, or homozygous LIF-knockout mice will be studied for their pituitary responses to stress.